AI Article Synopsis

  • Chronic liver disease and hepatocellular carcinoma (HCC) pose significant health risks with few effective treatments, largely due to the absence of suitable experimental models for research.
  • The study introduces a human liver cell-based model that accurately reflects a clinical prognostic liver signature (PLS), which helps predict the progression of liver disease to HCC.
  • By validating the PLS with animal models and patient samples, researchers identify nizatidine, an H2 receptor blocker, as a promising treatment for advanced liver disease and as a preventive measure against HCC, revealing new therapeutic targets through advanced analysis techniques.

Article Abstract

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2, CLEC5A, MARCO liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448834PMC
http://dx.doi.org/10.1038/s41467-021-25468-9DOI Listing

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